(NIH) - 12/24/2012 - A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking — they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient.
"For the first time, we have shown that split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light," explained Ming-Hu Han, Ph.D., of the Mount Sinai School of Medicine, New York City, a grantee of NIH’s National Institute of Mental Health (NIMH). "These results add to mounting clues about the mechanism of fast-acting antidepressant responses."
Han, Eric Nestler, M.D., Ph.D.,of Mount Sinai, and colleagues, report on their study online, Dec. 12, 2012, in the journal Nature.
In a companion article, NIMH grantees Kay Tye, Ph.D., of the Massachusetts Institute of Technology, Cambridge, Mass., and Karl Deisseroth, M.D., Ph.D., of Stanford University, Stanford, Calif., used the same cutting-edge technique to control mouse brain activity in real time. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by daily presentations of chronic, unpredictable mild physical stressors, instead of by shorter-term exposure to severe social stress.
Prior to the new studies, Han's team suspected that a telltale pattern — rapid firing of neurons that secrete the chemical messenger dopamine in a key circuit hub — makes an animal vulnerable to the depression-like effects of acute severe stress, and that slower firing supports resilience. But they lacked direct, real-time evidence.
To pinpoint cause-and-effect, they turned to a research technology pioneered by Deisseroth, called optogenetics. It melds fiber optics and genetic engineering to precisely control the activity of a specific brain circuit in a living, behaving animal. Genetically modified viruses are used to inject light-reactive proteins, borrowed from primitive organisms like algae, to make the circuitry similarly light-responsive.
The researchers had previously shown that neurons in the reward circuit hub deep in the brain, called the ventral tegmental area (VTA), fire at normal rates in social stress-resilient mice, but at high rates in social stress-susceptible mice. So they embedded an LED-lit optical fiber aimed at the VTA circuitry of genetically modified resilient mice to convert them into susceptible mice by triggering high firing rates.
Normally, it takes 10 days of repeated encounters with a dominant animal — an experimental procedure called social defeat stress — to induce depression-related behaviors. Even after that, some mice emerge seemingly unscathed. But these resilient animals — in which the reward circuit had been genetically modified for optogenetic control — instantly succumbed to a long-lasting depression-like syndrome after light pulses triggered neural activity mimicking the high firing rates seen in the susceptible animals.
In subsequent experiments, using similar optogenetic strategies, the researchers discovered that inhibiting the reward circuit activity pattern in stress-susceptible mice instantly converted them into stress-resilient animals. The reward circuit projects from the VTA to an area in the center front of the brain, called the nucleus accumbens. This study suggests that dopamine neurons firing at high rates in this specific circuit projection encode a signal for susceptibility to depression induced by acute, severe stress. By contrast, a circuit projection from the VTA to the prefrontal cortex, in the top front of the brain (see diagram), was found to serve an opposite function
Depression in humans often stems from milder stressors over longer periods of time. Tye and Deisseroth used optogenetics to probe reward circuit workings related to depression-like behaviors in rodents exposed to stressors like white noise, crowded housing, or continuous darkness or illumination. Exposure to some of these milder stressors lasted 10 weeks, compared to the 10-days of social defeat stress.
"We sought to mimic gradual, stress-induced transitions to depressed-like states, as are often seen clinically," explained Deisseroth, who is a practicing psychiatrist as well as a neuroscientist.
In contrast to the Han-Nestler results after social defeat stress, following 10 weeks of unpredictable chronic mild stress, optogentically inducing high firing rates in VTA dopamine neurons instantly reversed such depression-like behaviors induced by chronic mild stressors — and vice versa. Also opposite to the social defeat stress findings, optogenetically inhibiting VTA dopamine neurons induced depression-like states.
"The variable effects that stressors of different types induce in the dopamine system may point to the need for distinct treatment strategies for patients whose depressions stem from different types of experiences," said Tye, who is leading a research group studying the neural underpinnings of motivational and emotional processing.
When Tye and Deisseroth infused agents that block binding of the chemical messenger glutatmate in the nucleus accumbens, they produced an antidepressant response – mice struggled more to escape the stressor. They note that this is consistent with the effects of the fast-acting antidepressant ketamine, which similarly blocks glutamate.
While optogenetics is providing insights into rapid antidepressant mechanisms, the technique is not suitable for treatment of depression in humans.
"These stunning demonstrations that depression-like states can literally be switched on and off underscore that context — stressor type and intensity — is pivotal in the workings of the neurons and circuit implicated," said NIMH Director Thomas R. Insel, M.D. "These new, precise circuit breakers are advancing our understanding of how specific brain pathways regulate behavior."

RIVERWOODS, Ill.- (BUSINESS WIRE) - 12/5/2012 -The Discover U.S. Spending Monitor declined 2.7 points to 95.4 in November from 98.1 in October, reflecting lower consumer confidence in personal finances. However, consumers indicated that they intend to spend more in December during the holiday season. The Monitor is a 5-year-old daily poll tracking economic confidence and spending intentions of nearly 8,200 consumers throughout the month. Consumers Maintain Economic Confidence
The percentage of consumers rating the U.S. economy as good or excellent remained the same as October at 18 percent, up 10 percentage points from November 2011.
In November 2012, 51 percent of consumers viewed the economy as poor, an 11-point decrease from November 2011.
Female respondents who rated the economy as good or excellent in November increased 2 percentage points to 18 percent compared to October. However, male respondents who rated the economy as good or excellent declined 3 percentage points from October, also to 18 percent.
Remaining at a Monitor high, 35 percent of respondents expect the economy to improve, a 16-point year over year improvement from November 2011.
Consumers with an income of greater than $75,000 and those making between $40,000 and $75,000 both reported a decline in expectations of the economy getting better (down 2 points to 44 percent from October and down 1 percentage point to 34 percent, respectively). However, those making less than $40,000, who felt the economy was getting better, increased 3 percentage points to 31 percent. Outlook on Personal Finances Declines
Consumer outlook on personal finances declined from October to November 2012, but remained up year over year.
Consumers rating their personal finances as good or excellent declined 2 percentage points in November from the previous month to 35 percent. However, this is 2 percentage points higher than November 2011.
While the percent of respondents who expect their personal finances to improve in the future declined 2 points from October to 26 percent, this is 7 percentage points higher than November 2011.
Respondents between ages 18 to 39 who rate their personal finances as poor increased 7 points from October to 28 percent. Consumers Intend to Spend More in December
Despite a decline in confidence about their personal finances, 39 percent of consumers are gearing up for the holidays and have plans to increase their spending in December. This is up 9 percentage points from last month and is typical this time of year. Twelve percent of consumers also plan on increasing their discretionary personal spending such as going out to dinner and the movies, up 3 percentage points from last month.
However, consumers plan to offset their discretionary spending in other areas.
On major personal purchases such as a vacation, 46 percent expect to spend less, up 1 percentage point from October.
On household expenses, such as gas and groceries, 9 percent of consumers expect to spend less next month, up 2 percentage points from October.
Consumers also plan to spend less on household improvements next month, a 2-point increase from October to 49 percent.
42 percent of respondents intend to save or invest less in December, up 4 percentage points from last month. About Discover U.S. Spending Monitor
The Discover U.S. Spending Monitoris a monthly index of
consumer spending intentions and capacity that is based on interviews
with a random sample of 8,200 U.S. adults conducted at a rate of 275 per
night. In addition to spending, the survey asks consumers their opinions
on the U.S. economy and their personal finances. The Monitor began in
May 2007 with a base index of 100. Surveys are conducted by Rasmussen
Reports, an independent survey research firm (http://www.rasmussenreports.com).